DEVELOPMENTAL TOXICOLOGY EXPLORATORY (R21) RESEARCH GRANTS Release Date: June 14, 2001 RFA: RFA-ES-01-006 National Institute of Environmental Health Sciences (http://www.niehs.nih.gov) The American Chemistry Council (http://www.americanchemistry.com) Letter of Intent Date: July 17, 2001 Application Receipt Date: August 17, 2001 THIS RFA USES THE "MODULAR GRANT" AND "JUST-IN-TIME" CONCEPTS. IT INCLUDES DETAILED MODIFICATIONS TO STANDARD APPLICATION INSTRUCTIONS THAT MUST BE USED WHEN PREPARING APPLICATIONS IN RESPONSE TO THIS RFA. PURPOSE Recent advances in developmental biology, molecular biology and genomics present unique and timely opportunities to examine the site and mechanism of action of potential environmental developmental toxicants and to thereby set the stage for intervention and prevention strategies. The overall objective of this Request for Applications (RFA) is therefore to stimulate research on the mechanism of action of developmental toxicants using the state of the art tools of genomics, proteomics and model organisms including transgenic and gene knock out genetic animal models. This objective will be achieved by stimulating the interaction/collaboration of developmental toxicologists with developmental biologists, molecular biologists and geneticists in order to fully integrate these new research directions and to expand our knowledge on the mode of action of developmental toxicants. The new information obtained from these interactions will be used to accelerate research in developmental toxicology, advance new approaches in molecular epidemiology and improve qualitative and quantitative risk assessment processes for evaluating the potential for exposure induced developmental defects. This RFA is jointly supported by the National Institute of Environmental Health Sciences (NIEHS) and the American Chemistry Council (ACC). The NIEHS supports research into the role of environmental agents in the etiology of disease and dysfunction. The ACC is a not-for-profit organization established with the funding support of member companies of the U.S. chemical industry. The ACC has affirmed its commitment to Responsible Care and the American Public’s right to know by initiating a Long-Range Research Initiative (LRI) program support by $100 million over a five-year period. The LRI seeks to increase the knowledge of the potential risks that chemicals have on human health and the environment. Thus, this RFA is a unique collaboration of Government and Industry interested in improving the health of the American people by improving the quantity and the quality of the data on potential developmental toxicants that is available for use in the risk assessment process. HEALTHY PEOPLE 2010 The Public Health Service (PHS) is committed to achieving the health promotion and disease prevention objectives of "Healthy People 2010," a PHS led national activity for setting priority areas. This RFA: Developmental Toxicology Exploratory (R21) Research Grants," is related to several areas of emphasis in the disease prevention objectives. Potential applicants may obtain a copy of "Healthy People 2010" at http://www.health.gov/healthypeople ELIGIBILITY REQUIREMENTS Applications may be submitted by domestic and foreign, for-profit and non- profit organizations, public and private, such as universities, colleges, hospitals, laboratories, units of State and local governments, and eligible agencies of the Federal government. Racial/ethnic minority individuals, women, and persons with disabilities are encouraged to apply as Principal Investigators. SPECIAL REQUIREMENTS Letter of Authorization Because the domestic applications will be co-funded by the National Institutes of Health (NIH) and the American Chemistry Council (ACC), all applicants should submit a brief letter to the NIH indicating that the application and the summary statements for such applications can be shared with the ACC. Letters of authorization should be prepared by the Principal Investigator and co-signed by the official for the applicant organization. This letter should be submitted as a cover letter accompanying the application. Periodic Meetings Upon initiation of this program, the NIH and the American Chemistry Council plans to sponsor periodic meetings to encourage exchange of information among investigators, to foster collaborative efforts among program grantees, and to identify resources that would enhance the productivity of grantees. For this purpose, applicants should request travel funds for a two-day meeting each year, the timing and location of which will be announced. Applicants should include in their applications a statement indicating their willingness to participate in such meetings and, as appropriate, to cooperate with other researchers. MECHANISM OF SUPPORT This RFA will use the NIH R21 Exploratory/Developmental award mechanism. The objective of the Exploratory/Developmental Grant (R21) mechanism is to encourage applications for one-time grants to support innovative, high- risk/high-impact research requiring preliminary testing or development, exploration of the use of approaches and concepts new to a particular substantive area, research and development of new technologies, techniques or methods, or initial research and development of data upon which significant future research may be built. Applications will be considered as high impact if they demonstrate the potential for ground-breaking, precedent-setting significance, and high risk because they either lack sufficient preliminary data to ensure their feasibility, or involve using a new model system or technique. While this RFA is intended to encourage innovation and high impact research, and while minimal preliminary data are expected to be described in the application, applications should clearly indicate that the proposed research and/or development is scientifically sound, that the qualifications of the investigators are appropriate, and that resources available to the investigators are adequate. As the R21 grant project cannot be renewed, if sufficient data are generated during the term of the award, investigators could then apply for further funding through regular research grant, e.g., the research project grant (R01) mechanism. Specific application instructions have been modified to reflect the purpose and nature of this mechanism, as well as to accommodate the "Modular Grant" and "Just-In-Time" streamlining efforts being implemented by the NIH. Complete and detailed instructions and information on Modular Grant applications can be found at the website http://grants.nih.gov/grants/funding/modular/modular.htm. FUNDS AVAILABLE The total estimated funds available for this RFA is approximately $2 million that will support up to 15 awards. The annual funding plans of the NIEHS and the ACC have included, respectively, $1.5 million and $500,000 for each of two years to fund applications awarded in response to this RFA. This level of support is dependent on the receipt of a sufficient number of applications of high scientific merit. Awards will be for up to $100,000 per year (direct costs) for up to two years. The amount and time must be justified in the application. BACKGROUND This RFA is jointly supported by the National Institute of Environmental Health Sciences (NIEHS) and the American Chemistry Council (ACC), U.S.A. The NIEHS supports research into the role of environmental agents in the etiology of disease and dysfunction. The support of research on reproductive and developmental toxicology is a primary area of interest to the mission of the NIEHS. The ACC is an independent, not-for-profit organization established with the funding support of member companies of the U.S. chemical industry. The ACC has affirmed its commitment to Responsible Care? and the American Public’s right to know by initiating a Long-Range Research Initiative (LRI) program supported by $100 million over a five-year period. The LRI seeks to increase the knowledge of the potential risks that chemicals have on human health and the environment. The present initiative RFA addresses the mutual research goals of the NIEHS and the ACC to improve the quantity, quality, and timeliness of data from investigations on the mechanisms of developmental toxicants. Thus, this jointly sponsored RFA represents a unique collaboration of Government and Industry to support novel, high potential research that will contribute to the improvement of the health of the American people by improving the quantity and quality of the data on developmental toxicants that is available for use in the risk assessment process. A number of developmental components and processes involved in the organization of a metazoan body plan are shared between invertebrates and vertebrates, as described in a recent review (Scientific Frontiers in Developmental Toxicity and Risk Assessment: National Academy Press, Washington, D.C., 2000). Genes are shared across phyla that control processes such as dorsoventral dimension, organogenesis of limbs, eyes, heart, visceral mesoderm, and gut, cytodifferentiation in neurogenesis and myogenesis, and segmentation. There are approximately 17 cell signaling pathways identified that operate in early, mid, and late development in diverse species. In invertebrates such as the fruitfly (Drosophilia sp.) and the nematode worm (C. elegans), null (functional deletion) mutations in these morphogenetic and signaling pathways are often lethal. In mammals (mice), the genes encoding most components of these pathways have undergone duplication and slight diversification, leading to redundancy in the pathways. Null mutants are not always lethal, and may result in specific local losses that closely resemble those associated with human developmental defects. These defects reflect those times and places in development where a deleted component is not overlapped by a redundant component. It is anticipated that many of the kinds of defects that occur in developmental programs might arise from altered cell signaling pathways leading to alterations in selective gene expression, cell secretion, cell proliferation, and/or cell migration. Recent technological advances in genomics, including the recent sequencing of the genome of the human and a number of other species, have provided valuable information on the similarities and differences in the number and organization of genes amongst species. The new knowledge now in hand will allow the investigation of gene expression during development using RNA isolated from the specific organs of embryos and fetuses of the various species amenable to laboratory modeling. The use of DNA micro-array technologies to assess changes in gene expression is a rapidly growing research area that will have a large impact on many fields, including developmental toxicology. This technology will allow a global genomic/proteomic assessment of how an organism responds to a specific stress, drug, or toxicant. Data generated in these experiments will provide information on cellular networks of responding genes, help define important target molecules and pathways for toxicity investigations, as well as providing information on future biomarkers of toxic exposure and/or effect. Experiments using micro-array technology will help define the complex genomic regulatory circuitry and metabolic pathways within a cell, tissue and organ that respond to specific stressors. This technology may be able to help define the cascade of biochemical and molecular events that define pathways that lead to modulation and repair of a prenatal insult, thus preventing the occurrence of developmental toxicity. The science of proteomics promises to take over where genomics leaves off and provide data on tissue and time specific protein expression as well as post translational modifications altering protein activity. Indeed, it is feasible that the integration of functional genomics and proteomics in the discipline of metabonomics will soon provide global profiles and signatures of cellular metabolism for advancing new approaches to metabolic toxicology, in general, and developmental toxicology, in particular. The use of these new technologies (genomics and proteomics) and new surrogate humanized model systems in developmental toxicology will undoubtedly have a major impact on toxicology research within next decade and beyond. They offer the opportunity to markedly expand on our ability to develop a thorough understanding of the basic mechanisms of development as well as an improved knowledge of species differences which will undoubtedly and significantly contribute to improved public health via protective intervention and prevention strategies. RESEARCH OBJECTIVES The objectives of this RFA are to use the new technologies described in this RFA and appropriate model organisms to develop a more complete description of the mechanism of action of specific toxicants. This includes the toxicants interaction with specific molecular components of cellular or developmental processes in the conceptus and the consequences of those interactions for the function of the cellular or developmental process and the outcome, namely the developmental defect, recognized as either a structural malformation or functional deficit. It is anticipated that accomplishment of this goal will require the interaction and collaboration of developmental biologists, molecular biologists and developmental toxicologists. These multi-, intra- and inter- disciplinary collaborations are strongly encouraged by this RFA. The research objectives of the R21 mechanism used in this RFA are to support: 1) innovative, high-risk research, requiring preliminary testing or development, 2) exploration of new approaches or concepts to a particular substantive area, 3) research and development of new technologies, techniques or methods, or 4) initial research and development of data upon which significant future research may be built, i.e., the data should have a high level of impact on the field. The project research and/or development aims and scope can be relevant to any of the developmental toxicology science areas relevant to the mission areas supported by the research agenda of the NIEHS and the ACC as described below. In general, it is expected that the new approaches proposed for this RFA will consider the use of candidate chemicals that have been well characterized in vivo with respect to their sites of toxicity and dose responses. This RFA, in particular, seeks to explore a diversity of proposed modes of action and chemical classes in order to evaluate the broadest possible range of effects on developing embryos. The well-studied dioxin and dioxin-like substances will not receive priority consideration in this regard. The molecular approaches proposed should be related to survival (viability) or to a structural or functional defect in the embryo or fetus in order to determine exposures that lead to adaptation or repair verses those that lead to toxic manifestations. Relatively few toxicants have been sufficiently evaluated for effects on signaling pathway effects during development in mammals (e.g., cyclopamine and retinoic acid), but the potential for interference in these key cell signaling pathways is considered to be highly feasible. Such interference should be evaluated for impact on functional tissue or organ physiology or morphogenesis in the fetus, neonate, adolescent or adult individual. It is considered highly important that consideration be given to whether or not the observed effects on genes or gene activity occur similarly across species and are manifest as developmental defects. It is also important that consideration be given to understanding the time course and dose-response relationships between genetic, functional and morphogenetic effects across species since these data are critically important to risk assessment applications. To enhance the applicability to risk assessment, study designs that use environmentally relevant doses of test chemicals are encouraged, especially those that will provide sound data extending into the low dose portion of the dose response curve, i.e., in the region beneath traditionally observed NOAELs (No Observed Adverse Effect Levels) or LOAELs (Lowest Observed Adverse Effect Levels). It is anticipated that proposals using chemicals that have supportive data on developmental toxicity in rodent models and/or humans will be of compelling interest in this regard. Experimental models may include laboratory models studied for the conservation of the cell signaling transduction pathways (Drosophilia, C. elegans, zebrafish, etc.), species and strains normally used in toxicolology studies, and genetically sensitized/transgenic models with altered signal transduction pathways. In any event, any application that is submitted in response to this RFA should include appropriate justification(s) for the selection of chemical(s), dose(s) and experimental model(s). Applications are solicited in, but not limited to, the following areas. o Characterization of global gene expression profiles in specific organs/tissues of model organisms associated with the normal range of development and after a developmentally toxic exposure. The relationship between the changes in gene expression and the developmental lesion should be assessed. o Use of genomic and proteomic approaches to understand the effects of developmental toxicants on growth factor signaling and cross talk between and among signaling pathways. o Evaluation of specific signal transduction pathways and the associated genetic regulatory circuits as sites of action of developmental toxicants using model organisms and/or genomics, and the development of causal relationships to the developmental lesion(s). o Characterization of molecular stress and checkpoint pathways as sites of action of developmental toxicants and the elucidation of causal relationships between pathway alterations and dysmorphogenesis. o Use of genomic and proteomic profiling to show species and tissue specific toxicity of developmental toxicants that do not translate across species. o Application of genomic and proteomic technologies to examine the role and mechanism of oxidative damage from chemical exposure in the etiology of dysmorphogenesis or embryo lethality. o Use of forward and reverse mutagenesis studies in model organisms to determine the genes altered by specific developmental toxicants and the relationship of the altered gene activity to dysmorphogenesis. o Use of genetically sensitized models, including transgenic and gene knock- out animal models, to determine the potential for interactions between chemical exposures and genetic susceptibility that increase the risk for developmental toxicity. o Use of microarray and proteomic analysis to examine the effects of mixtures of toxicants with similar or different mechanisms of action and to compare the molecular results with dysmorphogenesis caused by the mixtures and individual components. o Analysis of systems responsible for the metabolism and transport of chemicals to the fetal compartment and their relationship to differences in embryonic survival, morphogenesis, or functional defects leading to morbidity. o The use of genomic approaches to examine fetal programming of modifications associated with exposure(s) to (an) environmental agent(s) during development that may result in functional changes later in life. It should be noted that for the purpose of this RFA research is limited to animal models and in vitro approaches that will provide mechanistic information on exposure to environmental agents during development and how that leads to lethality or dysmorphogenesis. Proposals to screen chemicals without regard to related studies on the specific mechanism of actions of the chemical(s) studied are not responsive to this RFA and will not be accepted. Epidemiological and clinical studies are considered non-responsive to this specific RFA. It is anticipated that such research may be the focus of future RFA initiatives. INCLUSION OF WOMEN AND MINORITIES IN RESEARCH INVOLVING HUMAN SUBJECTS It is the policy of the NIH that women and members of minority groups and their sub-populations must be included in all NIH-supported biomedical and behavioral research projects involving human subjects, unless a clear and compelling rationale and justification are provided indicating that inclusion is inappropriate with respect to the health of the subjects or the purpose of the research. This policy results from the NIH Revitalization Act of 1993 (Section 492B of Public Law 103-43). All investigators proposing research involving human subjects should read the UPDATED "NIH Guidelines for Inclusion of Women and Minorities as Subjects in Clinical Research," published in the NIH Guide for Grants and Contracts on August 2, 2000 (http://grants.nih.gov/grants/guide/notice-files/NOT-OD-00-048.html), a complete copy of the updated Guidelines is available at http://grants.nih.gov/grants/funding/women_min/guidelines_update.htm The revisions relate to NIH defined Phase III clinical trials and require: a) all applications or proposals and/or protocols to provide a description of plans to conduct analyses, as appropriate, to address differences by sex/gender and/or racial/ethnic groups, including subgroups if applicable, and b) all investigators to report accrual, and to conduct and report analyses, as appropriate, by sex/gender and/or racial/ethnic group differences. INCLUSION OF CHILDREN AS PARTICIPANTS IN RESEARCH INVOLVING HUMAN SUBJECTS It is the policy of NIH that children (i.e., individuals under the age of 21) must be included in all human subjects research conducted or supported by the NIH unless there are scientific and ethical reasons not to include them. This policy applies to all initial (Type 1) applications submitted for receipt dates after October 1, 1998. All investigators proposing research involving human subjects should read the "NIH Policy and Guidelines on the Inclusion of Children as Participants in Research Involving Human Subjects" that was published in the NIH Guide for Grants and Contracts, March 6, 1998, and is available at: http://grants.nih.gov/grants/guide/notice-files/not98-024.html Investigators also may obtain copies of these policies from the program staff listed under INQUIRIES. Program staff may also provide additional relevant information concerning the policy. URLS IN NIH GRANT APPLICATIONS OR APPENDICES All applications and proposals for NIH funding must be self-contained within specified page limitations. Unless otherwise specified in an NIH solicitation, internet addresses (URLs) should not be used to provide information necessary to the review because reviewers are under no obligation to view the Internet sites. Reviewers are cautioned that their anonymity may be compromised when they directly access an Internet site. PUBLIC ACCESS TO RESEARCH DATA THROUGH THE FREEDOM OF INFORMATION ACT The Office of Management and Budget (OMB) Circular A-110 has been revised to provide public access to research data through the Freedom of Information Act (FOIA) under some circumstances. Data that are (1) first produced in a project that is supported in whole or in part with Federal funds and (2) cited publicly and officially by a Federal agency in support of an action that has the force and effect of law (i.e., a regulation) may be accessed through FOIA. It is important for applicants to understand the basic scope of this amendment. NIH has provided guidance at: http://grants.nih.gov/grants/policy/a110/a110_guidance_dec1999.htm Applicants may wish to place data collected under this RFA (PA) in a public archive, which can provide protections for the data and manage the distribution for an indefinite period of time. If so, the application should include a description of the archiving plan in the study design and include information about this in the budget justification section of the application. In addition, applicants should think about how to structure informed consent statements and other human subjects procedures given the potential for wider use of data collected under this award. LETTER OF INTENT Prospective applicants are asked to submit, by July 6, 2001, a letter of intent that includes a descriptive title of the proposed project, the name, address, and telephone number of the Principal Investigator, the identities of other key personnel and participating institutions if planned collaborations are known, and the number and title of this RFA. Although a letter of intent is not required, is not binding, and does not enter into the review of subsequent application, the information that it contains allows NIEHS staff to estimate the potential review workload and plan the review. The letter of intent is to be sent to: Ethel B. Jackson, D.D.S. Chief, Scientific Review Branch (EC-30) Division of Extramural Research and Training Office of Program Operations National Institute of Environmental Health Sciences P.O. Box 12233, 111 T.W. Alexander Drive Research Triangle Park, NC 27709 Telephone: (919) 541-7846 FAX: (919) 541-2503 Email: jackson4@niehs.nih.gov APPLICATION PROCEDURES Applicants are strongly encouraged to contact the program contacts listed under INQUIRIES with any questions regarding their proposed project. The research grant application form PHS 398 (rev. 4/98) is to be used in applying for these grants with the modifications noted below. Application kits are available at most institutional offices of sponsored research and may be obtained from the Division of Extramural Outreach and Information Resources, National Institutes of Health, 6701 Rockledge Drive, MSC-7910, Bethesda, MD 20892-7910, telephone 301/710-0267, email GrantsInfo@nih.gov. Applications are also available on the World Wide Web at: http://grants.nih.gov/grants/forms.htm SPECIFIC INSTRUCTIONS FOR MODULAR GRANT APPLICATIONS The modular grant concept establishes specific modules in which direct costs may be requested as well as a maximum level for requested budgets. Only limited budgetary information is required under this approach. The just-in- time concept allows applicants to submit certain information only when there is a possibility for an award. It is anticipated that these changes will reduce the administrative burden for the applicants, reviewers, and Institute staff. The following instructions are to be used in conjunction with the information accompanying application form PHS 398 (rev. 4/98), they refer only to selected items in the application form. All PHS 398 requirements should be followed, with the exception of those items affected by the following instructions. Applications not conforming to the requested format will be returned to the applicant without review. FACE PAGE Item 2, Check the box marked Yes and type the RFA code number (RFA ES-01- 006) and title ( Developmental. Toxicology Exploratory Grants (R21) Program) on this line. Item 6: Up to a total of two years of support may be requested. Items 7a and 7b: These items should be completed indicating Direct Costs ($100,000) and Total Costs [$100,000 plus Facilities and Administrative (F&A) costs] for the initial budget period. Items 8a and 8b: These items should be completed indicating the Direct (i.e., $200,000) and Total Costs (i.e., $200,000 plus F&A) for the entire proposed period of support. DETAILED BUDGET FOR THE INITIAL BUDGET PERIOD Do not complete Form Page 4 of the PHS 398. It is not required and will not be accepted with the application. BUDGET FOR THE ENTIRE PROPOSED PERIOD OF SUPPORT Do not complete the categorical budget table on Form Page 5 of the PHS 398. It is not required and will not be accepted with the application. NARRATIVE BUDGET JUSTIFICATION Prepare a Modular Grant Budget Narrative page. (See http://grants.nih.gov/grants/funding/modular/modular.htm for sample pages.) At the top of the page, enter the total direct costs requested for each year. This is not a Form page. Under Personnel, list all project personnel, including their names, percent of effort, and roles on the project. No individual salary information should be provided. However, the applicant should use the NIH appropriation language salary cap and the NIH policy for graduate student compensation in developing the budget request. For Consortium/Contractual costs, provide an estimate of total costs (direct plus facilities and administrative) for each year, each rounded to the nearest $1,000. List the individuals/organizations with whom consortium or contractual arrangements have been made, the percent effort of all personnel, and the role on the project. Indicate whether the collaborating institution is foreign or domestic. The total cost for a consortium/contractual arrangement is included in the overall requested modular direct cost amount. Include the Letter of Intent to establish a consortium. BIOGRAPHICAL SKETCH The Biographical Sketch provides information used by reviewers in the assessment of each individual"s qualifications for a specific role in the proposed project, as well as to evaluate the overall qualifications of the research team. A biographical sketch is required for all key personnel, following the instructions below. No more than three pages may be used for each person. A sample biographical sketch may be viewed at: http://grants.nih.gov/grants/funding/modular/modular.htm. - Complete the educational block at the top of the form page, - List position(s) and any honors, - Provide information, including overall goals and responsibilities, on research projects ongoing or completed during the last three years, - List selected peer-reviewed publications, with full citations CHECKLIST This page should be completed and submitted with the application. If the F&A rate agreement has been established, indicate the type of agreement and the date. All appropriate exclusions must be applied in the calculation of the F&A costs for the initial budget period and all future budget years. The applicant should provide the name and phone number of the individual to contact concerning fiscal and administrative issues if additional information is necessary following the initial review. OTHER SUPPORT Do not complete this section. It is not required and will not be accepted with the application. RESEARCH PLAN Do not exceed a total of 10 pages inclusive of the following sections: Specific Aims, Background and Significance, Preliminary Studies/Progress Report (evidence of feasibility), and Research Design and Methods. Pertinent subject selection and recruitment information (e.g., inclusion of women, minorities, children), as it impacts on study design, should also be included. Tables, figures and photographs are included in the 10 page limitation. Item a, SPECIFIC AIMS The applicant should begin with a statement that justifies the designation of the application as an Exploratory/Developmental Research Grant as defined under the PURPOSE section of this program announcement. The instructions for this section suggest that the applicant state the hypotheses to be tested. Since some applications submitted in response to this RFA may also be design- or problem-driven (e.g., development of novel technologies), or need-driven (initial research to develop a body of data upon which future research will build), hypothesis testing per se may not be the driving force in developing such a proposal and, therefore, may not be applicable. Thus, the application should state the hypotheses, design, problem and/or need which will drive the proposed research. Submission of an application under this RFA precludes concurrent submission to the NIH of another application containing substantially the same research plan. Item b, BACKGROUND AND SIGNIFICANCE In this section it is important to identify clearly how the application addresses the specific objectives of this program announcement. For example, identify briefly how this application relates to the purpose of the R21 mechanism as stated in this RFA (i.e., highly innovative, high risk/high impact research, exploration of the use of approaches and concepts new to a particular substantive area, research and development of new technologies, techniques or methods, or initial research and development of a body of data upon which significant future research may be built). Item c, PRELIMINARY STUDIES/PROGRESS REPORT Minimal preliminary data are expected for an Exploratory/Developmental Grant application. Item d, RESEARCH DESIGN AND METHODS Fully describe the research design and methods. In many cases, an Exploratory/Developmental Grant mechanism will support novel research in an area or the research and development of new technologies. Where appropriate, specific criteria by which to judge the feasibility of novel approaches (including milestones that will mark progress) should be explicitly described in this section. LITERATURE CITED APPENDIX Appendix materials may not be used to circumvent the page limitations. Letters of support are not part of the appendix. However, letters of support may be used to establish the Principal Investigator"s research as separate and distinct from those of a former mentor or to denote collaborative or consultant relationships. Up to three publications, submitted manuscripts or abstracts may also be included. Five copies of appendix materials should be submitted. (Refer to PHS 398 application for additional Appendix guidelines.) The RFA label available in the PHS 398 (rev 4/98) application form must be affixed to the bottom of the face page of the application. Type the RFA number on the label. Failure to use this label could result in delayed processing of the application such that it may not reach the review committee in time for review. In addition, the RFA title and number must be typed on line 2 of the face page of the application form and the YES box must be marked. The sample RFA label available at: http://grants.nih.gov/grants/funding/phs398/label-bk.pdf has been modified to allow for this change. Please note this is in pdf form. Submit a signed, typewritten original of the application, including the Checklist, and three signed, photocopies, in one package to: CENTER FOR SCIENTIFIC REVIEW NATIONAL INSTITUTES OF HEALTH 6701 ROCKLEDGE DRIVE, ROOM 1040 MSC 7710 BETHESDA, MD 20892-7710 BETHESDA, MD 20817 (for express/courier service) At the time of submission, please send two additional copies of the application to: Ethel B. Jackson, D.D.S. Chief, Scientific Review Branch (EC-30) Division of Extramural Research and Training Office of Program Operations National Institute of Environmental Health Sciences P.O. Box 12233, 111 T.W. Alexander Drive Research Triangle Park, NC 27709 Telephone: (919) 541-7846 FAX: (919) 541-2503 Email: jackson4@niehs.nih.gov Applications must be received by the application receipt date listed in the heading of this RFA. If an application is received after that date, it will be returned to the applicant without review. The Center for Scientific Review (CSR) will not accept any application in response to this RFA that is essentially the same as one currently pending initial review, unless the applicant withdraws the pending application. The CSR will not accept any application that is essentially the same as one already reviewed. This does not preclude the submission of substantial revisions of applications already reviewed, but such applications must include an introduction addressing the previous critique. REVIEW CONSIDERATIONS Upon receipt, applications will be reviewed for completeness by the CSR and for responsiveness to this RFA by NIEHS and ACC staff. Incomplete and/or non-responsive applications will be returned to the applicant without further consideration. Applications that are complete and responsive to the RFA will be evaluated for scientific and technical merit by an appropriate peer review group convened by the NIEHS in accordance with review criteria stated below. As part of the initial merit review, all applications will receive a written critique and undergo a process in which only those applications deemed to have the highest scientific merit, generally the top-half of applications under review, will be discussed, assigned a priority score, and receive a second level of review by the National Advisory Environmental Health Sciences (NAEHS) Council. Review Criteria The goals of NIH-supported research are to advance the understanding of biological systems, improve the control of disease, and enhance health. In the written comments reviewers will be asked to discuss the following aspects of the application in order to judge the likelihood that the proposed research will have a substantial impact on the pursuit of these goals. Each of these criteria will be addressed and considered in the assignment of the overall score, weighting them as appropriate for each application. Note that the application does not need to be strong in all categories to be judged likely to have major scientific impact and thus deserve a high priority score. For example, an investigator may propose to carry out important work that by its nature is not innovative but is essential to move a field forward. (1) Significance. Does this study address an important problem? If the aims of the application are achieved, how will scientific knowledge be advanced? What will be the effect of these studies on the concepts or methods that drive this field? (2) Approach. Are the conceptual framework, design, methods, and analyses adequately developed, well integrated, and appropriate to the aims of the project? Does the applicant acknowledge potential problem areas and consider alternative tactics? (3) Innovation. Does the project employ novel concepts, approaches or methods? Are the aims original and innovative? Does the project challenge existing paradigms or develop new methodologies or technologies? (4) Investigator. Is the investigator appropriately trained and well suited to carry out this work? Is the work proposed appropriate to the experience level of the Principal Investigator and other researchers (if any)? (5) Environment. Does the scientific environment in which the work will be done contribute to the probability of success? Do the proposed experiments take advantage of unique features of the scientific environment or employ useful collaborative arrangements? Is there evidence of institutional support? In addition to the above criteria, in accordance with NIH policy, all applications will also be reviewed with respect to the following: - The adequacy of plans to include both genders, minorities and their subgroups, and children as appropriate for the scientific goals of the research. Plans for the recruitment and retention of subjects will also be evaluated. - The reasonableness of the proposed budget and duration in relation to the proposed research. - The adequacy of the proposed protection for humans, animals or the environment, to the extent they may be adversely affected by the project proposed in the application. SCHEDULE Letter of Intent: July 17, 2001 Application Receipt: August 17, 2001 NIEHS Committee Review: October/November, 2001 Council Review: February 11-12, 2001 Earliest Funding: April 1, 2002 AWARD CRITERIA Applications will compete with all other approved applications submitted in response to this RFA for the available funds provided by the NIEHS and the ACC. The following will be considered in making funding decisions: the quality of the proposed project as determined by peer review, program priority and balance among research areas solicited by this RFA and the availability of funds. In addition, the following factors will also be considered for applications assigned to the NIEHS in response to this jointly sponsored NIEHS/ACC program RFA: o potential for ground-breaking, precedent setting significance of the proposed research, with particular emphasis on novel and innovative approaches that clearly require additional preliminary data for their value to be established, o potential to stimulate new research concepts or directions of high importance to biomedical/behavioral problems, or providing a technique/system of wide applicability to developmental toxicology research. INQUIRIES Potential applicants are encouraged to call the NIEHS staff members listed in the program announcement regarding the areas of science relevant to this RFA that the NIEHS/ACC program supports. The opportunity to clarify any issues or questions from potential applicants is welcome. Direct inquiries regarding programmatic issues to: Michael E. McClure, Ph.D. or Jerry Heindel, Ph.D. Organs and Systems Toxicology Branch Division of Extramural Research and Training National Institute of Environmental Health Sciences P.O. Box 12233, EC-23 111 T.W. Alexander Drive (for express/courier service) Research Triangle Park, NC 27709 Telephone: (919) 541-1442 or (919) 541-0781 FAX: (919) 541-5064 Email: mm461n@nih.gov or heindelj@niehs.nih.gov Direct inquiries regarding fiscal matters to: Ms. Jackie Russell Grants Management Specialist Grants Management Branch Office of Program Operations Division of Extramural Research and Training National Institute of Environmental Health Sciences P. O. Box 12233, EC-22 111 T.W. Alexander Drive, (for express/courier service) Research Triangle Park, NC 27709 Telephone: (919) 541-0751 FAX: (919) 541-2860 Email: russell@niehs.nih.gov AUTHORITY AND REGULATIONS This program is described in the Catalog of Federal Domestic Assistance No. 93.113 and 93.115. Awards are made under authorization of Sections 301 and 405 of the Public Health Service Act, as amended (42 USC 241 and 284) and administered under NIH grants policies and Federal Regulations 42 CFR 52 and 45 CFR Part 74 and 92. This program is not subject to the intergovernmental review requirements of Executive Order 12372 or Health Systems Agency review. The Public Health Service (PHS) strongly encourages all grant and contract recipients to provide a smoke-free workplace and promote the non-use of all tobacco products. In addition, Public Law 103-227, the Pro Children Act of 1994, prohibits smoking in certain facilities (or in some cases, any portion of a facility) in which regular or routine education, library, day care, health care or early childhood development services are provided to children. This is consistent with the PHS mission to protect and advance the physical and mental health of the American people.


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NIH Funding Opportunities and Notices



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